U.S. patent application number 14/401095 was filed with the patent office on 2015-05-28 for process for making amino acid compounds.
This patent application is currently assigned to Genentech, Inc.. The applicant listed for this patent is Genentech, Inc.. Invention is credited to Travis Remarchuk.
Application Number | 20150148559 14/401095 |
Document ID | / |
Family ID | 48483247 |
Filed Date | 2015-05-28 |
United States Patent
Application |
20150148559 |
Kind Code |
A1 |
Remarchuk; Travis |
May 28, 2015 |
PROCESS FOR MAKING AMINO ACID COMPOUNDS
Abstract
The invention provides new processes for making and purifying
amino acid compounds, which are useful in the preparation of AKT
inhibitors used in the treatment of diseases such as cancer,
including the compound
(S)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cy-
clopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-one.
Inventors: |
Remarchuk; Travis; (South
San Francisco, CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Genentech, Inc. |
South San Francisco |
CA |
US |
|
|
Assignee: |
Genentech, Inc.
South San Francisco
CA
|
Family ID: |
48483247 |
Appl. No.: |
14/401095 |
Filed: |
May 17, 2013 |
PCT Filed: |
May 17, 2013 |
PCT NO: |
PCT/US2013/041687 |
371 Date: |
November 13, 2014 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
61648534 |
May 17, 2012 |
|
|
|
Current U.S.
Class: |
560/25 ; 560/30;
560/38; 560/51; 562/449 |
Current CPC
Class: |
C07C 67/343 20130101;
C07C 229/30 20130101; C07C 269/06 20130101; C07B 2200/07 20130101;
Y02P 20/55 20151101; C07C 67/313 20130101; C07C 269/04 20130101;
C07C 271/22 20130101; C07C 269/06 20130101; C07C 271/22 20130101;
C07C 67/343 20130101; C07C 69/738 20130101 |
Class at
Publication: |
560/25 ; 560/30;
560/51; 562/449; 560/38 |
International
Class: |
C07C 269/06 20060101
C07C269/06; C07C 271/22 20060101 C07C271/22; C07C 229/30 20060101
C07C229/30; C07C 269/04 20060101 C07C269/04; C07C 67/313 20060101
C07C067/313 |
Claims
1. A process comprising reducing a compound of formula II, or a
salt thereof: ##STR00032## wherein: R.sup.1 and R.sup.2 are
independently hydrogen, C.sub.1-C.sub.12 alkyl or an amino
protecting group to form a compound of formula I: ##STR00033## or a
salt thereof.
2. The process of claim 1, further comprising hydrolyzing a
compound of formula III, or salt thereof: ##STR00034## wherein:
R.sup.3 is optionally substituted C.sub.1-C.sub.12 alkyl, to form a
compound of formula II.
3. The process of claim 2, further comprising reacting a compound
of formula IV, or a salt or tautomer thereof: ##STR00035## with
--NHR.sup.1R.sup.2 or a salt thereof, to form a compound of formula
III, or a salt thereof.
4. The process of claim 3, wherein said compound --NHR.sup.1R.sup.2
is --NH(isopropyl).
5. The process of claim 3 further comprising contacting a compound
of formula V or a salt thereof: ##STR00036## with HCO.sub.2R.sup.4,
wherein R.sup.4 is optionally substituted C.sub.1-C.sub.12 alkyl,
or a salt thereof, under basic conditions, to form a compound of
formula IV, or a salt thereof.
6. The process of claim 5, wherein said basic conditions comprise a
base selected from hydroxide or alkoxide base.
7. The process of claim 1, wherein R.sup.1 is an amino protecting
group.
8. The process of claim 1, wherein said amino protecting group is
selected from acetyl, trifluoroacetyl, phthalimide, benzyl,
triphenylmethyl, benzylidenyl, p-toluenesulfonyl, p-methoxybenzyl,
tert-butyloxycarbonyl, 9-fluorenylmethyloxycarbonyl and
carbobenzyloxy.
9. The process of claim 1, wherein R.sup.1 is tert-butyloxycarbonyl
and R.sup.2 is isopropyl.
10. The process of claim 1, wherein said reducing comprises
contacting a compound of formula II, or a salt thereof, with a
metal catalyst and hydrogen gas.
11. The process of claim 10, wherein said metal catalyst is a
ruthenium, rhodium, or palladium catalyst.
12. The process of claim 10, wherein said metal catalyst is
[(S)-BINAPRuCl(benzene)]Cl.
13. The process of claim 1, wherein R.sup.2 is an amino protecting
group.
14. The process of claim 1, wherein R.sup.2 is C.sub.1-C.sub.12
alkyl.
15. The process of claim 1, wherein R.sup.2 is isopropyl.
16. The process of claim 1, wherein said reducing comprises
reducing a compound of formula IIb, or a salt thereof: ##STR00037##
to form said compound of formula I or a salt thereof.
17. A compound of formula VI: ##STR00038## or salt thereof,
wherein: R.sup.1 and R.sup.2 are independently hydrogen,
C.sub.1-C.sub.12 alkyl or an amino protecting group; and R.sup.5 is
hydrogen or an optionally substituted C.sub.1-C.sub.12 alkyl.
18. The compound of claim 17, wherein R.sup.1 is hydrogen or
t-butyloxycarbonyl; R.sup.2 is C.sub.1-C.sub.12 alkyl; and R.sup.5
is hydrogen or C.sub.1-C.sub.12 alkyl.
19. The compound of claim 17, wherein R.sup.1 is hydrogen; R.sup.2
is isopropyl; and R.sup.5 is hydrogen or ethyl.
20. The compound of claim 17, having the formula VIb: ##STR00039##
or a salt thereof wherein R.sup.1 is hydrogen or an amino
protecting group.
21. The compound of claim 17, wherein R.sup.1 is
t-butyloxycarbonyl.
22. The compound of claim 20, wherein R.sup.1 is
t-butyloxycarbonyl.
Description
PRIORITY OF INVENTION
[0001] This application claims priority to U.S. Provisional
Application No. 61/648,534 that was filed on 17 May 2012. The
entire content of this provisional application is hereby
incorporated herein by reference.
FIELD OF THE INVENTION
[0002] Disclosed herein are processes for making and purifying
amino acid compounds for the synthesis of inhibitors of AKT kinase
activity.
BACKGROUND OF THE INVENTION
[0003] The Protein Kinase B/Akt enzymes are a group of
serine/threonine kinases that are overexpressed in certain human
tumors. International Patent Application Publication Number WO
2008/006040 and U.S. Pat. No. 8,063,050 discuss a number of
inhibitors of AKT, including the compound
(S)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cy-
clopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-one
(GDC-0068). While processes described in WO 2008/006040 and U.S.
Pat. No. 8,063,050 are useful in providing hydroxylated
cyclopenta[d]pyrimidine compounds as AKT protein kinase inhibitors,
alternative or improved processes are needed, including for large
scale manufacturing of these compounds.
BRIEF SUMMARY OF THE INVENTION
[0004] Disclosed are processes for preparing, separating and
purifying compounds detailed herein. Compounds provided herein
include AKT protein kinase inhibitors, salts thereof, and
intermediates useful in the preparation of such compounds.
[0005] One aspect includes a process comprising reducing a compound
of formula II, or a salt thereof:
##STR00001##
wherein R.sup.1 and R.sup.2 are defined herein to form a compound
of formula I:
##STR00002##
or a salt thereof.
[0006] Another aspect includes a process comprising hydrolysing a
compound of formula III, or salt thereof:
##STR00003##
wherein R.sup.3 is defined herein to form a compound of formula II
or salt thereof.
[0007] Another aspect includes a process comprising reacting a
compound of formula IV, or a salt or tautomer thereof:
##STR00004##
with --NHR.sup.1R.sup.2 or a salt thereof, to form a compound of
formula III, or a salt thereof.
[0008] Another aspect includes a process comprising contacting a
compound of formula V or a salt thereof,
##STR00005##
with HCO.sub.2R.sup.4, wherein R.sup.4 is defined herein, to form a
compound of formula IV, or a salt thereof.
[0009] Another aspect includes a compound of formula VI:
##STR00006##
or salt thereof, wherein R.sup.1, R.sup.2 and R.sup.5 are defined
herein.
[0010] Another aspect includes a compound having the formula
VIa:
##STR00007##
or a salt thereof, wherein R.sup.1 is defined herein.
[0011] Another aspect includes a compound having the formula
VIb:
##STR00008##
or a salt thereof, wherein R.sup.1 is defined herein.
BRIEF DESCRIPTION OF THE FIGURES
[0012] FIG. 1 shows the solved single crystal x-ray analysis of
(E)-3-(tert-butoxycarbonyl(isopropyl)amino)-2-(4-chlorophenyl)acrylic
acid, which shows the E-configuration.
DETAILED DESCRIPTION OF THE INVENTION
[0013] Reference will now be made in detail to certain embodiments
of the invention, examples of which are illustrated in the
accompanying structures and formulas. While the invention will be
described in conjunction with the enumerated embodiments, it will
be understood that they are not intended to limit the invention to
those embodiments. On the contrary, the invention is intended to
cover all alternatives, modifications, and equivalents which may be
included within the scope of the present invention as defined by
the claims. In the event that one or more of the incorporated
literature and similar materials differs from or contradicts this
application, including but not limited to defined terms, term
usage, described techniques, or the like, this application
controls.
[0014] "Acyl" means a carbonyl containing substituent represented
by the formula --C(O)--R in which R is hydrogen, alkyl, a
cycloalkyl, a heterocyclyl, cycloalkyl-substituted alkyl or
heterocyclyl-substituted alkyl wherein the alkyl, alkoxy,
cycloalkyl and heterocyclyl are independently optionally
substituted and as defined herein. Acyl groups include alkanoyl
(e.g., acetyl), aroyl (e.g., benzoyl), and heteroaroyl (e.g.,
pyridinoyl).
[0015] The term "alkyl" as used herein refers to a saturated linear
or branched-chain monovalent hydrocarbon radical of one to twelve
carbon atoms, and in another embodiment one to six carbon atoms,
wherein the alkyl radical may be optionally substituted
independently with one or more substituents described herein.
Examples of alkyl groups include, but are not limited to, methyl
(Me, --CH.sub.3), ethyl (Et, --CH.sub.2CH.sub.3), 1-propyl (n-Pr,
n-propyl, --CH.sub.2CH.sub.2CH.sub.3), 2-propyl (i-Pr, i-propyl,
--CH(CH.sub.3).sub.2), 1-butyl (n-Bu, n-butyl,
--CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 2-methyl-1-propyl (i-Bu,
butyl, --CH.sub.2CH(CH.sub.3).sub.2), 2-butyl (s-Bu, s-butyl,
--CH(CH.sub.3)CH.sub.2CH.sub.3), 2-methyl-2-propyl (t-Bu, t-butyl,
--C(CH.sub.3).sub.3), 1-pentyl (n-pentyl,
--CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 2-pentyl
(--CH(CH.sub.3)CH.sub.2CH.sub.2CH.sub.3), 3-pentyl
(--CH(CH.sub.2CH.sub.3).sub.2), 2-methyl-2-butyl
(--C(CH.sub.3).sub.2CH.sub.2CH.sub.3), 3-methyl-2-butyl
(--CH(CH.sub.3)CH(CH.sub.3).sub.2), 3-methyl-1-butyl
(--CH.sub.2CH.sub.2CH(CH.sub.3).sub.2), 2-methyl-1-butyl
(--CH.sub.2CH(CH.sub.3)CH.sub.2CH.sub.3), 1-hexyl
(--CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 2-hexyl
(--CH(CH.sub.3)CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 3-hexyl
(--CH(CH.sub.2CH.sub.3)(CH.sub.2CH.sub.2CH.sub.3)),
2-methyl-2-pentyl (--C(CH.sub.3).sub.2CH.sub.2CH.sub.2CH.sub.3),
3-methyl-2-pentyl (--CH(CH.sub.3)CH(CH.sub.3)CH.sub.2CH.sub.3),
4-methyl-2-pentyl (--CH(CH.sub.3)CH.sub.2CH(CH.sub.3).sub.2),
3-methyl-3-pentyl (--C(CH.sub.3)(CH.sub.2CH.sub.3).sub.2),
2-methyl-3-pentyl (--CH(CH.sub.2CH.sub.3)CH(CH.sub.3).sub.2),
2,3-dimethyl-2-butyl (--C(CH.sub.3).sub.2CH(CH.sub.3).sub.2),
3,3-dimethyl-2-butyl (--CH(CH.sub.3)C(CH.sub.3).sub.3, 1-heptyl,
1-octyl, and the like.
[0016] The term "alkylene" as used herein refers to a linear or
branched saturated divalent hydrocarbon radical of one to twelve
carbon atoms, and in another embodiment one to six carbon atoms,
wherein the alkylene radical may be optionally substituted
independently with one or more substituents described herein.
Examples include, but are not limited to, methylene, ethylene,
propylene, 2-methylpropylene, pentylene, and the like.
[0017] The term "alkenyl" as used herein refers to a linear or
branched-chain monovalent hydrocarbon radical of two to twelve
carbon atoms, and in another embodiment two to six carbon atoms,
with at least one site of unsaturation, i.e., a carbon-carbon,
sp.sup.2 double bond, wherein the alkenyl radical may be optionally
substituted independently with one or more substituents described
herein, and includes radicals having "cis" and "trans"
orientations, or alternatively, "E" and "Z" orientations. Examples
include, but are not limited to, ethylenyl or vinyl
(--CH.dbd.CH.sub.2), allyl (--CH.sub.2CH.dbd.CH.sub.2), 1-propenyl,
1-buten-1-yl, 1-buten-2-yl, and the like.
[0018] The term "alkynyl" as used herein refers to a linear or
branched monovalent hydrocarbon radical of two to twelve carbon
atoms, and in another embodiment two to six carbon atoms, with at
least one site of unsaturation, i.e., a carbon-carbon, sp triple
bond, wherein the alkynyl radical may be optionally substituted
independently with one or more substituents described herein.
Examples include, but are not limited to, ethynyl (--C.ident.CH)
and propynyl (propargyl, --CH.sub.2C.ident.CH).
[0019] The term "alkoxy" refers to a linear or branched monovalent
radical represented by the formula --OR in which R is alkyl,
alkenyl, alkynyl or cycloalkyl, which can be further optionally
substituted as defined herein. Alkoxy groups include methoxy,
ethoxy, propoxy, isopropoxy, mono-, di- and tri-fluoromethoxy and
cyclopropoxy.
[0020] "Amino" means primary (i.e., --NH.sub.2), secondary (i.e.,
--NRH), tertiary (i.e., --NRR) and quaternary (i.e.,
--N.sup.+RRRX.sup.-) amines, that are optionally substituted, in
which R is independently alkyl, alkoxy, a cycloalkyl, a
heterocyclyl, cycloalkyl, -substituted alkyl or
heterocyclyl-substituted alkyl wherein the alkyl, alkoxy,
cycloalkyl and heterocyclyl are as defined herein Particular
secondary and tertiary amines are alkylamine, dialkylamine,
arylamine, diarylamine, aralkylamine and diaralkylamine wherein the
alkyls and aryls are as herein defined and independently optionally
substituted. Particular secondary and tertiary amines are
methylamine, ethylamine, propylamine, isopropylamine, phenylamine,
benzylamine dimethylamine, diethylamine, dipropylamine and
diisopropylamine.
[0021] The terms "cycloalkyl," "carbocycle," "carbocyclyl" and
"carbocyclic ring" as used herein are used interchangeably and
refer to saturated or partially unsaturated cyclic hydrocarbon
radical having from three to twelve carbon atoms, and in another
embodiment three to eight carbon atoms. The term "cycloalkyl"
includes monocyclic and polycyclic (e.g., bicyclic and tricyclic)
cycloalkyl structures, wherein the polycyclic structures optionally
include a saturated or partially unsaturated cycloalkyl ring fused
to a saturated, partially unsaturated or aromatic cycloalkyl or
heterocyclic ring. Examples of cycloalkyl groups include, but are
not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
cycloheptyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, and the
like. Bicyclic carbocycles include those having 7 to 12 ring atoms
arranged, for example, as a bicyclo[4,5], [5,5], [5,6] or [6,6]
system, or as bridged systems such as bicyclo[2.2.1]heptane,
bicyclo[2.2.2]octane, and bicyclo[3.2.2]nonane. The cycloalkyl may
be optionally substituted independently with one or more
substituents described herein.
[0022] The term "aryl" as used herein means a monovalent aromatic
hydrocarbon radical of 6-20 carbon atoms derived by the removal of
one hydrogen atom from a single carbon atom of a parent aromatic
ring system. Aryl includes bicyclic radicals comprising an aromatic
ring fused to a saturated, partially unsaturated ring, or aromatic
carbocyclic or heterocyclic ring. Exemplary aryl groups include,
but are not limited to, radicals derived from benzene, naphthalene,
anthracene, biphenyl, indene, indane, 1,2-dihydronapthalene,
1,2,3,4-tetrahydronapthalene, and the like. Aryl groups may be
optionally substituted independently with one or more substituents
described herein.
[0023] The terms "heterocycle", "hetercyclyl" and "heterocyclic
ring" as used herein are used interchangeably and refer to a
saturated or partially unsaturated carbocyclic radical of 3 to 12
membered ring atoms in which at least one ring atom is a heteroatom
independently selected from nitrogen, oxygen and sulfur, the
remaining ring atoms being C, where one or more ring atoms may be
optionally substituted independently with one or more substituents
described below. One embodiment includes heterocycles of 3 to 7
membered ring atoms in which at least one ring atom is a heteroatom
independently selected from nitrogen, oxygen and sulfur, the
remaining ring atoms being C, where one or more ring atoms may be
optionally substituted independently with one or more substituents
described below. The radical may be a carbon radical or heteroatom
radical. The term "heterocycle" includes heterocycloalkoxy.
"Heterocyclyl" also includes radicals where heterocycle radicals
are fused with a saturated, partially unsaturated, or aromatic
carbocyclic or heterocyclic ring. Examples of heterocyclic rings
include, but are not limited to, pyrrolidinyl, tetrahydrofuranyl,
dihydrofuranyl, tetrahydrothienyl, tetrahydropyranyl,
dihydropyranyl, tetrahydrothiopyranyl, piperidino, morpholino,
thiomorpholino, thioxanyl, piperazinyl, homopiperazinyl,
azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl,
thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, 2-pyrrolinyl,
3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl,
1,3-dioxolanyl, pyrazolinyl, dithianyl, dithiolanyl,
dihydropyranyl, dihydrothienyl, dihydrofuranyl,
pyrazolidinylimidazolinyl, imidazolidinyl,
3-azabicyco[3.1.0]hexanyl, 3-azabicyclo[4.1.0]heptanyl,
azabicyclo[2.2.2]hexanyl, 3H-indolyl quinolizinyl and N-pyridyl
ureas. Spiro moieties are also included within the scope of this
definition. The heterocycle may be C-attached or N-attached where
such is possible. For instance, a group derived from pyrrole may be
pyrrol-1-yl (N-attached) or pyrrol-3-yl (C-attached). Further, a
group derived from imidazole may be imidazol-1-yl (N-attached) or
imidazol-3-yl (C-attached). Examples of heterocyclic groups wherein
2 ring carbon atoms are substituted with oxo (.dbd.O) moieties are
isoindoline-1,3-dionyl and 1,1-dioxo-thiomorpholinyl. The
heterocycle groups herein are optionally substituted independently
with one or more substituents described herein.
[0024] The term "heteroaryl" as used herein refers to a monovalent
aromatic radical of a 5-, 6-, or 7-membered ring and includes fused
ring systems (at least one of which is aromatic) of 5-10 atoms
containing at least one heteroatom independently selected from
nitrogen, oxygen, and sulfur. Examples of heteroaryl groups
include, but are not limited to, pyridinyl, imidazolyl,
imidazopyridinyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl,
tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl,
isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl,
benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl,
phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl,
purinyl, oxadiazolyl, triazolyl, thiadiazolyl, thiadiazolyl,
furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl,
benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, and
furopyridinyl. Spiro moieties are also included within the scope of
this definition. Heteroaryl groups may be optionally substituted
independently with one or more substituents described herein.
[0025] "Leaving group" refers to a portion of a first reactant in a
chemical reaction that is displaced from the first reactant in the
chemical reaction. Examples of leaving groups include, but are not
limited to, hydrogen, halogen, hydroxyl groups, sulfhydryl groups,
amino groups (for example --NRR, wherein R is independently alkyl,
alkenyl, alkynyl, cycloalkyl, phenyl or heterocyclyl and R is
independently optionally substituted), silyl groups (for example
--SiRRR, wherein R is independently alkyl, alkenyl, alkynyl,
cycloalkyl, phenyl or heterocyclyl and R is independently
optionally substituted), --N(R)OR (wherein R is independently
alkyl, alkenyl, alkynyl, cycloalkyl, phenyl or heterocyclyl and R
is independently optionally substituted), alkoxy groups (for
example --OR, wherein R is independently alkyl, alkenyl, alkynyl,
cycloalkyl, phenyl or heterocyclyl and R is independently
optionally substituted), thiol groups (for example --SR, wherein R
is independently alkyl, alkenyl, alkynyl, cycloalkyl, phenyl or
heterocyclyl and R is independently optionally substituted),
sulfonyloxy groups (for example --OS(O).sub.1-2R, wherein R is
independently alkyl, alkenyl, alkynyl, cycloalkyl, phenyl or
heterocyclyl and R is independently optionally substituted),
sulfamate groups (for example --OS(O).sub.1-2NRR, wherein R is
independently alkyl, alkenyl, alkynyl, cycloalkyl, phenyl or
heterocyclyl and R is independently optionally substituted),
carbamate groups (for example --OC(O).sub.2NRR, wherein R is
independently alkyl, alkenyl, alkynyl, cycloalkyl, phenyl or
heterocyclyl and R is independently optionally substituted), and
carbonate groups (for example --OC(O).sub.2RR, wherein R is
independently alkyl, alkenyl, alkynyl, cycloalkyl, phenyl or
heterocyclyl and R is independently optionally substituted).
Example sulfonyloxy groups include, but are not limited to,
alkylsulfonyloxy groups (for example methyl sulfonyloxy (mesylate
group) and trifluoromethylsulfonyloxy (triflate group)) and
arylsulfonyloxy groups (for example p-toluenesulfonyloxy (tosylate
group) and p-nitrosulfonyloxy (nosylate group)). Other examples of
leaving groups include substituted and unsubstituted amino groups,
such as amino, alkylamino, dialkylamino, hydroxylamino,
alkoxylamino, N-alkyl-N-alkoxyamino, acylamino, sulfonylamino, and
the like.
[0026] "Amino-protecting group" as used herein refers to groups
commonly employed to keep amino groups from reacting during
reactions carried out on other functional groups. Examples of such
protecting groups include carbamates, amides, alkyl and aryl
groups, imines, as well as many N-heteroatom derivatives which can
be removed to regenerate the desired amine group. Particular amino
protecting groups are Ac (acetyl), trifluoroacetyl, phthalimide, Bn
(benzyl), Tr (triphenylmethyl or trityl), benzylidenyl,
p-toluenesulfonyl, Pmb (p-methoxybenzyl), Boc
(tert-butyloxycarbonyl), Fmoc (9-fluorenylmethyloxycarbonyl) and
Cbz (carbobenzyloxy). One example includes Ac (acetyl),
trifluoroacetyl, phthalimide, Bn (benzyl), Tr (triphenylmethyl or
trityl), benzylidenyl, p-toluenesulfonyl, Pmb (p-Methoxybenzyl),
Fmoc (9-Fluorenylmethyloxycarbonyl) and Cbz (Carbobenzyloxy).
Further examples of these groups are found in: Wuts, P. G. M. and
Greene, T. W. (2006) Frontmatter, in Greene's Protective Groups in
Organic Synthesis, Fourth Edition, John Wiley & Sons, Inc.,
Hoboken, N.J., USA. The term "protected amino" refers to an amino
group substituted with one of the above amino-protecting
groups.
[0027] The term "substituted" as used herein means any of the above
groups (e.g., alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, aryl,
heterocyclyl and heteroaryl) wherein at least one hydrogen atom is
replaced with a substituent. In the case of an oxo substituent
(".dbd.O") two hydrogen atoms are replaced. "Substituents" within
the context of this invention include, but are not limited to,
halogen, hydroxy, oxo, cyano, nitro, amino, alkylamino,
dialkylamino, alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy,
substituted alkyl, thioalkyl, haloalkyl (including perhaloalkyl),
hydroxyalkyl, aminoalkyl, substituted alkenyl, substituted alkynyl,
substituted cycloalkyl, aryl, substituted aryl, heteroaryl,
substituted heteroaryl, heterocycle, substituted heterocycle,
--NR.sup.eR.sup.f, --NR.sup.eC(.dbd.O)R.sup.f,
--NR.sup.eC(.dbd.O)NR.sup.eR.sup.f,
--NR.sup.eC(.dbd.O)OR.sup.f--NR.sup.eSO.sub.2R.sup.f, --OR.sup.e,
--C(.dbd.O)R.sup.e--C(.dbd.O)OR.sup.e, --C(.dbd.O)NR.sup.eR.sup.f,
--OC(.dbd.O)NR.sup.eR.sup.f, --SR.sup.e, --SOR.sup.e,
--S(.dbd.O).sub.2R.sup.e, --OS(.dbd.O).sub.2R.sup.e,
--S(.dbd.O).sub.2OR.sup.e, wherein R.sup.e and R.sup.f are the same
or different and independently hydrogen, alkyl, substituted alkyl,
alkenyl, substituted alkenyl, alkynyl, substituted alkynyl,
cycloalkyl, substituted cycloalkyl, aryl, substituted aryl,
heteroaryl, substituted heteroaryl, heterocycle, substituted
heterocycle.
[0028] The term "halo" or "halogen" as used herein means fluoro,
chloro, bromo or iodo.
[0029] The term "a" as used herein means one or more.
[0030] Reference to "about" a value or parameter herein includes
(and describes) embodiments that are directed to that value or
parameter per se and in one embodiment plus or minus 20% of the
given value. For example, description referring to "about X"
includes description of "X".
[0031] "Pharmaceutically acceptable salts" include both acid and
base addition salts. Exemplary salts include, but are not limited,
to sulfate, citrate, acetate, oxalate, chloride, bromide, iodide,
nitrate, bisulfate, phosphate, acid phosphate, isonicotinate,
lactate, salicylate, acid citrate, tartrate, oleate, tannate,
pantothenate, bitartrate, ascorbate, succinate, maleate,
gentisinate, fumarate, gluconate, glucuronate, saccharate, formate,
benzoate, glutamate, methanesulfonate, ethanesulfonate,
benzenesulfonate, p-toluenesulfonate, and pamoate (i.e.,
1,1''-methylene-bis-(2-hydroxy-3-naphthoate)) salts. A
pharmaceutically acceptable salt may involve the inclusion of
another molecule such as an acetate ion, a succinate ion or other
counter ion. The counter ion may be any organic or inorganic moiety
that stabilizes the charge on the parent compound.
[0032] "Pharmaceutically acceptable acid addition salt" refers to
those salts which retain the biological effectiveness and
properties of the free bases and which are not biologically or
otherwise undesirable, formed with inorganic acids such as
hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,
carbonic acid, phosphoric acid and the like, and organic acids may
be selected from aliphatic, cycloaliphatic, aromatic, araliphatic,
heterocyclic, carboxylic, and sulfonic classes of organic acids
such as formic acid, acetic acid, propionic acid, glycolic acid,
gluconic acid, lactic acid, pyruvic acid, oxalic acid, malic acid,
maleic acid, maloneic acid, succinic acid, fumaric acid, tartaric
acid, citric acid, aspartic acid, ascorbic acid, glutamic acid,
anthranilic acid, benzoic acid, cinnamic acid, mandelic acid,
embonic acid, phenylacetic acid, methanesulfonic acid,
ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid,
salicyclic acid and the like.
[0033] "Pharmaceutically acceptable base addition salts" include
those derived from inorganic bases such as sodium, potassium,
lithium, ammonium, calcium, magnesium, iron, zinc, copper,
manganese, aluminum salts and the like. Particularly base addition
salts are the ammonium, potassium, sodium, calcium and magnesium
salts. Salts derived from pharmaceutically acceptable organic
nontoxic bases includes salts of primary, secondary, and tertiary
amines, substituted amines including naturally occurring
substituted amines, cyclic amines and basic ion exchange resins,
such as isopropylamine, trimethylamine, diethylamine,
triethylamine, tripropylamine, ethanolamine, 2-diethylaminoethanol,
tromethamine, dicyclohexylamine, lysine, arginine, histidine,
caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine,
glucosamine, methylglucamine, theobromine, purines, piperizine,
piperidine, N-ethylpiperidine, polyamine resins and the like.
Particularly organic non-toxic bases are isopropylamine,
diethylamine, ethanolamine, tromethamine, dicyclohexylamine,
choline, and caffeine.
[0034] The term "tautomer" or "tautomeric form" refers to
structural isomers of different energies which are interconvertible
via a low energy barrier. For example, proton tautomers (also known
as prototropic tautomers) include interconversions via migration of
a proton, such as keto-enol and imine-enamine isomerizations.
Valence tautomers include interconversions by reorganization of
some of the bonding electrons. One example of tautomers described
herein includes the two tautomers of compounds of formula IV and
IVa below.
##STR00009##
Additional specific tautomers include ethyl
2-(4-chlorophenyl)-3-hydroxyacrylate and ethyl
2-(4-chlorophenyl)-3-oxopropanoate.
[0035] Compounds of the present invention, unless otherwise
indicated, include compounds that differ only in the presence of
one or more isotopically enriched atoms. For example, compounds of
the present invention, wherein one or more hydrogen atoms are
replaced by deuterium or tritium, or one or more carbon atoms are
replaced by a .sup.13C or .sup.14C carbon atom, or one or more
nitrogen atoms are replaced by a .sup.15N nitrogen atom, or one or
more sulfur atoms are replaced by a .sup.33S, .sup.34S or .sup.36S
sulfur atom, or one or more oxygen atoms are replaced by a .sup.17O
or .sup.18O oxygen atom are within the scope of this invention.
[0036] One aspect includes a process that includes reducing a
compound of formula II or a salt thereof:
##STR00010##
wherein:
[0037] R.sup.1 and R.sup.2 are independently hydrogen,
C.sub.1-C.sub.12 alkyl or an amino protecting group; to form a
compound of formula I:
##STR00011##
or a salt thereof.
[0038] In certain embodiments, the process of reducing a compound
of formula II comprises reducing a compound of formula IIb or a
salt thereof to form a compound of formula I or a salt thereof:
##STR00012##
[0039] In certain embodiments, the process of reducing a compound
of formula II comprises reducing a compound of formula IIa or a
salt thereof to form a compound of formula I or a salt thereof:
##STR00013##
[0040] In certain embodiments of formulas II, IIa, or IIb, R.sup.1
is isopropyl and R.sup.2 is an amino protecting group, e.g., Boc
group.
[0041] In certain embodiments, the reducing comprises contacting a
compound of formula II, IIa, or IIb, or a salt thereof, with a
reducing agent.
[0042] Reducing agents (e.g., used in the preparation of a compound
of formula I) comprise a reducing agent capable of reducing an
alkene. In one embodiment, the reducing agent comprises metal
hydride (e.g., a boron, aluminum or lithium/aluminum hydride or an
alkoxy- or thioalkyl-lithium aluminum hydride, such as
LiAlH(OR).sub.3 where R is independently an alkyl, for example
LiAlH(OMe).sub.3, LiAlH(SMe).sub.3, or LiAlH(Otbutyl).sub.3)
reducing agent.
[0043] In another embodiment, the reducing agent promotes
asymmetric reduction (e.g., of the alkene of formula II, IIa, or
IIb, to formula I). The reducing agent may contain one or more
compounds or components, such as when a reagent that is capable of
hydrogen or hydride transfer is used in conjunction with an agent
that promotes or directs stereoselectivity of the hydrogen or
hydride transfer reaction, e.g., a stereoselective catalyst or
enzyme. Thus, in one aspect, the reducing agent comprises a
stereoselective reducing reagent comprising an agent that is
capable of hydrogen or hydride transfer and an agent that promotes
or directs stereoselectivity of the hydrogen or hydride transfer
reaction. In one aspect, the agent that promotes or directs
stereoselectivity of the hydrogen or hydride transfer reaction
comprises transition metal catalyst. In one aspect, the agent that
promotes or directs stereoselectivity of the hydrogen or hydride
transfer reaction comprises an enzyme.
[0044] In certain embodiments, the reducing agent comprises a metal
catalyst and hydrogen source. In certain embodiments, the metal
catalyst comprises a ruthenium, rhodium, or palladium catalyst. In
certain embodiments, the metal catalyst comprises
[(S)-BINAPRuCl(benzene)]Cl.
[0045] Sources of hydrogen include hydrogen gas, and other sources
used in transfer hydrogenation reactions, including water
(optionally with formate or acetate salts such as sodium formate),
diimide, hydrazine (or hydrazine hydrate), alcohols, such as
methanol, ethanol and isopropanol, cycloalkenes, such as
cyclohexene, cyclohexadiene, dihydronaphthalene and
dihydroanthracene, organic acids (optionally with an amine such as
trimethyl or triethylamine), such as formic acid, acetic acid or
phosphoric acid, silanes such as HSiR.sub.3 (where R is
independently an alkyl group, such as HSiMe.sub.3 and HSiEt.sub.3),
NADH, NADPH, FADH.sub.2, ammonium salts, such as ammonium formate
and ammonium chloride, and Hanztch esters such as those of the
formula:
##STR00014##
wherein R.sup.11, R.sup.12, R.sup.13 and R.sup.14 are independently
alkyl (In certain examples: R.sup.11 and R.sup.12 are methyl and
R.sup.13 and R.sup.14 are ethyl; R.sup.11 and R.sup.12 are methyl
and R.sup.13 and R.sup.14 are butyl; R.sup.11 is methyl, R.sup.12
is isopropyl and R.sup.13 and R.sup.14 are methyl; R.sup.11 and
R.sup.12 are methyl, R.sup.13 is methyl and R.sup.14 is t-butyl;
R.sup.11 and R.sup.12 are methyl and R.sup.13 and R.sup.14 are
methyl; R.sup.11 and R.sup.12 are methyl and R.sup.13 and R.sup.14
are isobutyl; R.sup.11 and R.sup.12 are methyl and R.sup.13 and
R.sup.14 are allyl.
[0046] In certain embodiments, the reaction of a compound of
formula II, IIa, or IIb, or a salt thereof, with a reducing agent
to provide a compound of formula I, or a salt thereof, is carried
out by a catalytic reduction reaction wherein the catalyst
comprises a metal catalyst such as a ruthenium catalyst, a rhodium
catalyst or a palladium catalyst to produce one or more chiral
centers. Examples of metal catalysts include, but are not limited
to, RuL.sub.3X (wherein X is a halogen, e.g., Cl) or RhL.sub.3Cl,
wherein L is a phosphine ligand, such as PR.sub.3, wherein R is
independently alkyl, alkenyl, alkynyl, cycloalkyl, aryl or
heterocyclyl, and wherein R is independently optionally
substituted, such as [RhCl(PPh.sub.3).sub.3].
[0047] Examples of ligands for the metal catalyst include, but are
not limited to DIOP, DIPAMP, BINAP, TolBINAP, XylBINAP, BPPFOH,
BPPM, BICHEP, BPPFOH, BICHHEP, BIPHEP, BIPHEMP, MeO-BIPHEP,
MOD-DIOP, CyDIOP, BCPM, MCCPM, NORPHOS, PYRPHOS (DEGUPHOS), BDPP
(SKEWPHOS), Me-DuPhos, Et-DuPhos, iPr-DuPhos, Me-BPE, Et-BPE,
iPr-BPE, o-Ph-HexaMeO-BIPHEP, RoPHOS, KetalPhos, BASPHOS,
Me-PennPhos, BINAPHANE, BICP, DIOP, BDPMI, T-Phos, SK-Phos, EtTRAP,
PrTRAP, PrTRAP, BuTRAP, PhTRAP, Josiphos, PPF-tBu.sub.2, Xyliphos,
FerroPHOS, FERRIPHOS, TaniaPhos, f-KetalPHos, Et-FerroTANE,
t-Bu-BISP, Ad-BisP, Cy-BisP, t-Bu-MiniPhos, Cy-MiniPhos,
iPr-MiniPhos, TangPhos, BIPNOR, Binapine, unsymmetrical BisP,
[2,2]PHANEPHOS, Ph-o-NAPHOS, spirOP, BINAPO, Ph-o-BINAPO, DIMOP,
and others described in Chi, Y, et. al, Modern Rhodium-Catalyzed
Organic Reactions, Ed. Evans, P.A., Wiley, 2005, Chapter 1.
Examples of metal catalysts include, but are not limited to
[(S)-BINAPRuCl(benzene)]Cl, [(R,R)TsDACH Ru(p-cymene)Cl] and
[(R,R)Teth-TsDPEN RuCl] or (R,R)Me.sub.2NSO.sub.2DPEN with
[RhCp*Cl.sub.2].sub.2. In another example, the catalyst is a
heterogeneous hydrogenation catalyst for example palladium on
carbon or palladium on aluminum oxide. In one example, the catalyst
is 5% Pd/C Type A405038 or 5% Pd/Al.sub.2O.sub.3 Type A302011 to
produce the cis isomer. Other suitable catalyst may be identified
by screening, e.g., based on desired stereoselectivity, reaction
rate and turnover. The reducing agent may comprise any suitable
hydrogen source or hydride source, such as formic acid or a boron
reducing agent or hydrogen gas.
[0048] In some examples, the hydrogen source is used in combination
with a metal catalyst comprising magnesium, sodium, ruthenium(II),
rhodium(III), iridium(III), nickel, platinum, palladium or a
combination thereof.
[0049] Another aspect includes the compound of formula I or a salt
thereof produced according to the process comprising reducing a
compound of formula II, IIa, or IIb, a salt thereof.
[0050] Another embodiment includes a process that includes
hydrolysing a compound of formula III, or salt thereof:
##STR00015##
wherein:
[0051] R.sup.3 is optionally substituted C.sub.1-C.sub.12 alkyl to
form a compound of formula II or a salt thereof.
[0052] In certain embodiments, the process of hydrolyzing a
compound of formula III, or salt thereof, to form a compound of
formula II or a salt thereof comprises hydrolysing a compound of
formula IIIa, or salt thereof.
##STR00016##
[0053] In certain embodiments, the process of hydrolyzing a
compound of formula III, or salt thereof, to form a compound of
formula II or a salt thereof comprises hydrolysing a compound of
formula IIIb, or salt thereof.
##STR00017##
[0054] In certain embodiments, the process of hydrolyzing a
compound of formula III, or a salt thereof, to form a compound of
formula II or a salt thereof comprises contacting a compound of
formula III, or a salt thereof, with aqueous base. Aqueous base
includes, for example, a mixture of base and water. Base used for
the hydrolysis includes hydroxide base. Examples of hydroxide base
for the hydrolysis include sodium hydroxide, potassium hydroxide
and ammonium hydroxide. The hydrolyzing reaction optionally further
comprises co-solvents to facilitate the reaction, including ethers,
such as tetrahydrofuran and MTBE, and alcohols, such as methanol,
ethanol, isopropanol, butanol and t-butyl alcohol, and combinations
thereof. In certain embodiments, the hydrolyzing reaction is
conducted in a mixture of ether, alcohol and water, for example, a
mixture of THF, methanol and water (for example, a mixture of each
in equal parts by volume).
[0055] Another aspect includes the compound of formula II or a salt
thereof produced according to the process comprising hydrolysing a
compound of formula III, or salt thereof.
[0056] Another embodiment includes a process comprising reacting a
compound of formula IV, or a salt or tautomer thereof:
##STR00018##
with --NHR.sup.1R.sup.2 or a salt thereof, to form a compound of
formula III, or a salt thereof.
[0057] In certain embodiments, the compound --NHR.sup.1R.sup.2 is
--NH(C.sub.1-C.sub.12 alkyl). In certain embodiments, the compound
--NHR.sup.1R.sup.2 is NH.sub.3 or a salt thereof. In certain
embodiments, the compound --NHR.sup.1R.sup.2 is a salt of NH.sub.3
selected from formate, carbonate, hydroxide, acetate, bromide,
carbamate, sulfate, chloride, fluoride, nitrate, phosphate and
thiosulfate. In certain embodiments, the compound
--NHR.sup.1R.sup.2 is ammonium formate. In certain embodiments, the
compound --NHR.sup.1R.sup.2 is --NH(isopropyl).
[0058] Another aspect includes the compound of formula III or a
salt thereof produced according to the process comprising reacting
a compound of formula IV, or a salt or tautomer thereof with
--NHR.sup.1R.sup.2 or a salt thereof.
[0059] Another embodiment includes a process comprising contacting
a compound of formula V or a salt thereof:
##STR00019##
with HCO.sub.2R.sup.4, wherein R.sup.4 is optionally substituted
C.sub.1-C.sub.12 alkyl, or a salt thereof, under basic conditions,
to form a compound of formula IV, or a salt thereof
[0060] In certain embodiments, R.sup.4 is C.sub.1-C.sub.6 alkyl. In
certain embodiments, R.sup.4 is ethyl.
[0061] In certain embodiments, the basic conditions include a
non-nucleophilic base. In certain embodiments, the base comprises
hydroxide, alkoxide, lithium alkyl bases or lithium amide bases. In
certain embodiments, the base comprises lithium diisopropylamide,
t-butyl lithium, sodium t-butoxide, potassium t-butoxide, ammonium
t-butoxide, sodium hydroxide, potassium hydroxide or ammonium
hydroxide. In certain embodiments, the base comprises potassium
t-butoxide. In certain embodiments, the basic conditions further
comprise a solvent such as a polar solvent, selected from alcohols,
ethers, amides or other suitable solvents or combinations thereof.
For example, ether or alcohol solvents are used, such as diethyl
ether, MTBE, methanol, ethanol or isopropanol. In one example, the
solvent is MTBE.
[0062] Another aspect includes the compound of formula IV or salt
thereof produced according to the process comprising contacting a
compound of formula V or a salt thereof with HCO.sub.2R.sup.4,
wherein R.sup.4 is optionally substituted C.sub.1-C.sub.12 alkyl,
or a salt thereof, under basic conditions.
[0063] Another embodiment includes a compound of formula VI:
##STR00020##
or salt thereof, wherein:
[0064] R.sup.1 and R.sup.2 are independently hydrogen,
C.sub.1-C.sub.12 alkyl or an amino protecting group; and
[0065] R.sup.5 is hydrogen or an optionally substituted
C.sub.1-C.sub.12 alkyl.
[0066] In certain embodiments of formula VI, R.sup.1 is hydrogen or
t-butyloxycarbonyl; R.sup.2 is C.sub.1-C.sub.12 alkyl; and R.sup.5
is hydrogen or C.sub.1-C.sub.12 alkyl.
[0067] In certain embodiments of formula VI, R.sup.1 is hydrogen;
R.sup.2 is isopropyl; and R.sup.5 is hydrogen or ethyl.
[0068] In certain embodiments, the compound of formula VI includes
a compound of the formula VIa:
##STR00021##
or a salt thereof wherein R.sup.1 is hydrogen or an amino
protecting group.
[0069] In certain embodiments, the compound of formula VI includes
a compound of the formula VIb:
##STR00022##
or a salt thereof wherein R.sup.1 is hydrogen or an amino
protecting group.
[0070] In certain embodiments, R.sup.1 in formula Va is
t-butyloxycarbonyl. In certain embodiments, R.sup.1 in formula Va
is hydrogen.
[0071] In certain embodiments of formulas I-III and VI, R.sup.1 is
an amino protecting group.
[0072] In certain embodiments of formulas I-III and VI, R.sup.2 is
an amino protecting group. In certain embodiments, R.sup.1 and
R.sup.2 are independently an amino protecting group. In certain
embodiments, R.sup.2 is Boc amino protecting group. In certain
embodiments, R.sup.1 and R.sup.2 are Boc amino protecting
group.
[0073] In certain embodiments of formulas I-III and VI, R.sup.2 is
C.sub.1-C.sub.12 alkyl. In certain embodiments, R.sup.1 is hydrogen
and R.sup.2 is C.sub.1-C.sub.12 alkyl.
[0074] In certain embodiments of formulas I-III and VI, R.sup.2 is
isopropyl. In certain embodiments, R.sup.1 is hydrogen and R.sup.2
is isopropyl. In certain embodiments, R.sup.1 is hydrogen and
R.sup.2 is amino protecting group. In certain embodiments, R.sup.1
is hydrogen and R.sup.2 is Boc amino protecting group.
[0075] In certain embodiments of formulas I-III and VI, R.sup.1 is
tert-butyloxycarbonyl and R.sup.2 is isopropyl.
[0076] In certain embodiments of formulas I-III and VI, R.sup.1 and
R.sup.2 are tert-butyloxycarbonyl.
[0077] In certain embodiments, the amino protecting group is
selected from acetyl, trifluoroacetyl, phthalimide, benzyl,
triphenylmethyl, benzylidenyl, p-toluenesulfonyl, p-methoxybenzyl,
tert-butyloxycarbonyl, 9-fluorenylmethyloxycarbonyl and
carbobenzyloxy.
[0078] The compounds detailed herein may contain one or more chiral
centers. Accordingly, if desired, such compounds can be prepared or
isolated as pure stereoisomers (such as individual enantiomers or
diastereomers, or as stereoisomer-enriched mixtures). All such
stereoisomers (and enriched mixtures) are included within the scope
of this invention, unless otherwise indicated. Pure stereoisomers
(or enriched mixtures) may be prepared using, for example,
optically active starting materials or stereoselective reagents
well-known in the art. Alternatively, racemic or
stereoisomer-enriched mixtures of such compounds can be separated
using, for example, chiral column chromatography, chiral resolving
agents, and the like.
[0079] Compounds detailed herein may be present as mixtures of
configurational or cis/trans isomers. For example, compounds of
formulas II, III and VI comprise mixtures of (E) and (Z) isomers,
as denoted by the wavy line. For example, compounds of formula II
include mixtures of formula IIa (the (Z) isomer) and IIb (the (E)
isomer), unless described otherwise, as shown below.
##STR00023##
[0080] For illustrative purposes, Scheme 1 shows a general method
for preparing the compounds of the present invention as well as key
intermediates. For a more detailed description of the individual
reaction steps, see the Examples section below. Those skilled in
the art will appreciate that other synthetic routes may be used to
synthesize the inventive compounds. Although specific starting
materials and reagents are depicted in the Scheme and discussed
below, other starting materials and reagents can be easily
substituted to provide a variety of derivatives and/or reaction
conditions. In addition, many of the compounds prepared by the
methods described below can be further modified in light of this
disclosure using conventional chemistry well known to those skilled
in the art.
##STR00024##
[0081] Scheme 1 shows general methods for preparing compounds of
formula I. Compound V is condensed with a compound of HC(O)OR.sup.4
to form compounds of formula IV. Further condensation of compounds
IV with an amine HNR.sup.1R.sup.2 forms compounds of formula III.
When R.sup.1 is hydrogen in compounds of formula III, additional
protection of the amine can be done to form protected compounds of
formula III (e.g., where R.sup.1 or R.sup.2 are independently an
amino protecting group, such as Boc), followed by hydrolysis of the
ester to form compounds of formula II. Asymmetric reduction of
compounds of formula II gives compounds of formula I. Optional
further deprotection of compound of formula I, when R.sup.1 and/or
R.sup.2 is an amino protecting group, e.g., a Boc group, leads to
compounds of formula I, wherein R.sup.1 and/or R.sup.2 are
hydrogen.
##STR00025##
[0082] Scheme 2 shows alternative general methods for preparing
compounds of formula I, wherein the (E)-isomer of compounds IIIb
and IIb are used.
[0083] Another aspect provides the use of compounds of formula I as
intermediates for preparing pharmaceutically active compounds, such
as the AKT inhibitors described in U.S. Pat. No. 8,063,050, issued
Nov. 22, 2011 to Mitchell et al. For example, as shown below in
Scheme 2, compounds of formula I can be used to prepare
(S)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cy-
clopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-one,
as described in U.S. Pat. No. 8,063,050, issued Nov. 22, 2011, as
described, for example, in Example 14, which is incorporated herein
by reference.
##STR00026##
[0084] Scheme 2 illustrates a method for making a compound of
formula 2.2. Compounds of formula 2.1, prepared as described in
U.S. Pat. No. 8,063,050, can be acylated with a compound of formula
I, for example where R.sup.1 is isopropyl and R.sup.2 is Boc, to
give an amide, which after optional functionalisation, such as by
deprotecting the Boc group, for example, gives compounds of formula
2.2, such as
(S)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cy-
clopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-one
where R.sup.1 is isopropyl and R.sup.2 is hydrogen.
[0085] Another aspect includes a process of producing a compound of
formula 2.2, or salt thereof,
##STR00027##
comprising reacting a compound of formula 2.1, or salt thereof,
##STR00028##
with a compound of formula Ia
##STR00029##
or salt thereof, to form a compound of formula 2.2.
[0086] Another aspect includes the compound of formula 2.2 or salt
thereof produced according to the process comprising reacting a
compound of formula 2.1, or salt thereof, with a compound of
formula Ia, or salt thereof.
[0087] Compositions comprising a compound as detailed herein, or
salt thereof, are also embraced by the invention. In one aspect, a
composition comprising a compound of formula VI, or a salt thereof,
is provided. In a particular variation, the composition comprises a
salt of a compound of formula VIa. In a particular variation, the
composition comprises a salt of a compound of formula VIb.
EXAMPLES
[0088] The invention can be further understood by reference to the
following examples, which are provided by way of illustration and
are not meant to be limiting.
Abbreviations used herein are as follows:
[0089] AcOH: Acetic Acid
[0090] Aq.: aqueous
[0091] DIPA: diisopropylamine
[0092] DIPEA: diisopropylethylamine
[0093] MTBE: methyl t-butyl ether
[0094] MsDPEN: N-methanesulfonyl-1,2-diphenylethylenediamine
[0095] TsDACH: N-(p-toluenesulfonyl)-1,2-diaminocyclohexane
[0096] Dppp: 1,3-Bis(diphenylphosphino)propan
[0097] PhME: toluene
[0098] DBU: 1,8-Diazobicyclo[5,40]undec-7-ene
Example 1
##STR00030##
[0099]
(S)-3-(tert-butoxycarbonyl(isopropyl)amino)-2-(4-chlorophenyl)propa-
noic acid
(E)-ethyl
3-((tert-butoxycarbonyl)(isopropyl)amino)-2-(4-chlorophenyl)acry-
late
[0100] Into a solution of ethyl formate (123.9 L, 1538.9 mol) in
MTBE (189 L) was added ethyl 4-chlorophenylacetate (120 kg, 604.1
mol). The mixture was stirred at 15-30.degree. C. for 30 min and
then a mixture of t-BuOK (136.8 kg, 1219.1 mol) in MTBE (1215.8 L)
was added while maintaining the internal temperature below
5.degree. C. The mixture was stirred between 0-10.degree. C. for
1.5 h. The reaction mixture was added to an aqueous solution of
hydrochloric acid (35%, 99.8 L in 560 L H.sub.2O) maintaining the
internal temperature below 10.degree. C. The mixture was stirred
for 30 min between 0-10.degree. C. until a final pH=2 was observed.
The layers were separated and the organic layer was washed with 25%
NaCl solution (496 L). The mixture was cooled to -5.degree. C. and
then isopropylamine (107.2 L, 1251.9 mol) and AcOH (70.5 L, 1233.3
mol) were slowly added maintaining the temperature <10.degree.
C. The mixture was stirred for 3 h at 0-10.degree. C. and then the
organic layer was washed with H.sub.2O (760 L), 15% aqueous
Na.sub.2CO.sub.3 (424 L) and then 25% aqueous NaCl (650 L). The
aqueous layer was separated and DMF (443 L) and DMAP (14.4 kg.
117.9 mol) were added to the organic solution. The mixture was then
heated to 60-65.degree. C. followed by slow addition of
(Boc).sub.2O (951.6 L, 4142 mol), DMF (228.6 L) and triethylamine
(263.0 L, 1821.8 mol) over 24 h. After stirring .about.6 h, the
mixture was cooled to room temperature and MTBE (1434 L), water
(1010 L) and 10% aqueous citric acid (938 L) were added. The
aqueous layer was separated and the mixture was washed by 25%
aqueous NaCl (984 L). The organic layer was then concentrated via
distillation to a minimum working volume (.about.240 L) while
maintaining the temperature below 50.degree. C. The organic layer
was then stirred for 5 h at 0-5.degree. C. and filtered. The filter
cake was washed with heptane (20.6 L) and dried to afford (E)-ethyl
3-((tert-butoxycarbonyl)(isopropyl)amino)-2-(4-chlorophenyl)acr-
ylate (148.55 kg, 63% yield over three steps) as a white solid.
(E)-3-(tert-butoxycarbonyhisopropyl)amino)-2-(4-chlorophenyl)acrylic
acid
[0101] (E)-ethyl
3-((tert-butoxycarbonyl)(isopropyl)amino)-2-(4-chlorophenyl)acrylate
(133.5 kg, 362.9 mol) was added into a mixture of H.sub.2O (252 L),
NaOH (58.25 kg, 1456 mol) and EtOH (383.5 L) stirred at room
temperature. The mixture was warmed to 40-45.degree. C. for 2.5 h
until a clear solution was formed. The mixture was concentrated to
a minimum working volume maintaining the temperature below
50.degree. C. The mixture was then cooled to 10-25.degree. C. and a
solution of HCl was added (842 L of 2N HCl and 11 L of 35% HCl)
until a final pH=2.about.4 was obtained. The aqueous layer was
separated and the organic layer was washed with 25% aqueous NaCl
(810 L). n-Heptane was added while distilling to form a suspension.
The product was collected and washed with n-heptane and dried at
40-45.degree. C. for .about.10 h to afford 110.7 kg (90.5% yield)
of
(E)-3-(tert-butoxycarbonyl(isopropyl)amino)-2-(4-chlorophenyl)acrylic
acid having 99.9 A % purity by HPLC. E-configuration was confirmed
using single crystal x-ray analysis (See FIG. 1).
(S)-3-(tert-butoxycarbonyl(isopropyl)amino)-2-(4-chlorophenyl)propanoic
acid
[0102] Into a thoroughly cleaned reactor was charged
(E)-3-(tert-butoxycarbonyl(isopropyl)amino)-2-(4-chlorophenyl)acrylic
acid (33 kg, 84.7 mol), EtOH (164.6 L), LiBF.sub.4(0.462 kg, 4.9
mol) and [(S)-BINAPRuCl(benzene)]Cl (0.043 kg, 0.049 mol) were
added. The mixture was degassed and then stirred for 24-26 h under
hydrogen (3.0-3.5 MPa) until IPC by HPLC showed no starting
material remained.
[0103] A solution of compound
(S)-3-(tert-butoxycarbonyl(isopropyl)amino)-2-(4-chlorophenyl)propanoic
acid (.about.20% assay in EtOH solution 138.7 kg in 680 kg EtOH)
was concentrated to 139-277 L below 50.degree. C. to which was
added EtOAc (999 L). The mixture was washed with 25% aqueous NaCl
(700 L.times.3) and then the organic layer concentrated to 555-694
L below 50.degree. C. To the solution was added silica thiol (8.30
kg) and the mixture was stirred for 14 h at 45-50.degree. C. After
cooling to 10-30.degree. C., the mixture was filtered and washed
with EtOAc (40 L). The filtrate was concentrated to 139 L below
50.degree. C. and n-heptane (485 L.times.2) was added in portions
with continuous distillation to form a suspension. The suspension
was stirred for 1.5 h at 45-50.degree. C. and stirred for 12-16 h
at -5 to 5.degree. C. The product was collected by filtration and
washed with n-heptane (229 L.times.4). The filter cake was dried
for 10 h at 40-45.degree. C. to afford compound
(S)-3-(tert-butoxycarbonyl(isopropyl)amino)-2-(4-chlorophenyl)propanoic
acid (126.29 kg, 91% yield and >99% ee) as a white solid.
.sup.1H NMR (400 MHz, MeOH-d.sub.4) .delta. 7.33 (s, 4H), 3.7-3.73
(3H), 3.44 (s, 1H), 1.44 (s, 9H), 1.07-1.09 (d, 3H), 0.96-0.98 (d,
3H).
Example 2
##STR00031##
[0104]
(S)-3-((bis-tert-butoxycarbonyl)amino)-2-(4-chlorophenyl)propanoic
acid
Ethyl 2-(4-chlorophenyl)-3-oxopropanoate
[0105] To an oven-dried, round bottom flask purged with nitrogen
containing a solution of 4-ethyl 2-(4-chlorophenyl)acetate (100 g,
0.51 mol, 1.0 equiv) in MTBE (1.0 L, 10 vol), was added the t-BuOK
(113.0 g, 1.0 mol, 2.0 equiv) portionwise at 0.degree. C. The
reaction mixture was stirred for 15 min at 0.degree. C. and then
ethyl formate (101.7 mL, 1.3 mol, 2.5 equiv) was added dropwise.
Reaction was monitored by HPLC (IPC by LCMS (m/z): [M].sup.+ shows
226.9). The reaction mixture was stirred at 0-10.degree. C. for 3 h
then quenched into the cold 2N aqueous HCl. The organic phase was
separated and washed with brine (3.times.300 mL). Concentration of
the organic phase under reduced pressure afforded the crude product
(91 g, 81% yield) as an unassigned mixture of the isomers
(.about.1:1 mixture of ethyl
2-(4-chlorophenyl)-3-oxopropanoate/ethyl
2-(4-chlorophenyl)-3-hydroxyacrylate) and brown oil. The crude
product mixture was used directly for next step without further
purification.
Ethyl 3-amino-2-(4-chlorophenyl)acrylate
[0106] A .about.1:1 mixture of ethyl
2-(4-chlorophenyl)-3-oxopropanoate/ethyl
2-(4-chlorophenyl)-3-hydroxyacrylate (50.0 g, 0.22 mol, 1.0 equiv)
and ammonium formate (69.6 g, 1.10 mol, 5.0 equiv) in EtOH (500 mL,
10 vol) was heated at 65.degree. C. for 8 h. Reaction was monitored
by HPLC (IPC by LCMS (m/z): [M].sup.+ shows 225.9). The reaction
mixture was then concentrated under reduced pressure to a minimal
working volume. The mixture was partitioned between cold water (200
mL) and EtOAc (200 mL). The organic phase was separated and washed
with saturated aqueous NaHCO.sub.3 (100 mL) and brine (3.times.100
mL). The organics were dried over anhydrous Na.sub.2SO.sub.4,
filtered and concentrated to give crude product ethyl
3-amino-2-(4-chlorophenyl)acrylate (42 g, 85% yield) as an
unassigned mixture of E/Z isomers (.about.1:1) and brown oil. The
crude product was used directly for next step without further
purification.
(E)-ethyl
3-((bis-tert-butoxycarbonyl)amino)-2-(4-chlorophenyl)acrylate
[0107] To the solution of ethyl 3-amino-2-(4-chlorophenyl)acrylate
(63.7 g, 0.28 mol, 1.0 equiv) in DMF (382 mL, 6 vol) was charged
triethylamine (85.0 g, 0.84 mol, 3.0 equiv) and DMAP (6.8 g, 0.056
mol, 0.2 equiv). A solution of Boc.sub.2O (305.6 g, 1.4 mol, 5.0
equiv) and DMF (255 mL, 4 vol) was added dropwise to the flask at
65.degree. C. over 1 h, and the resulting reaction mixture was
maintained at 65.degree. C. for .about.8 h. The reaction mixture
was then quenched by dropwise addition of saturated aqueous
NaHCO.sub.3 (130 mL) at room temperature and extracted with EtOAc
(260 mL). The organics were washed with brine (3.times.200 mL),
dried (Na.sub.2SO.sub.4), filtered and concentrated under reduced
pressure to afford the crude product (E)-ethyl
3-((bis-tert-butoxycarbonyl)amino)-2-(4-chlorophenyl)acrylate as
brown oil. Purification via chromatography (1:20, EtOAc/Petroleum
ether) gave pure product (63.7 g, 53% yield) as yellow oil. .sup.1H
NMR (400 MHz, CDCl.sub.3) .delta.: 7.62 (s, 1H), 7.31 (d, J=8.4 Hz,
2H), 7.18 (d, J=8.4 Hz, 2H), 4.24 (dd, J=7.2 Hz and J=14.2 Hz, 2H),
1.34 (s, 18H), 1.28 (t, J=6.8 Hz, 3H); MS-ESI (m/z): [M+Na].sup.+
448.0.
3-((bis-tert-butoxycarbonyl)amino)-2-(4-chlorophenyl)acrylic
acid
[0108] The (E)-ethyl
3-((bis-tert-butoxycarbonyl)amino)-2-(4-chlorophenyl)acrylate (73.4
g, 0.172 mol, 1.0 equiv) was stirred with NaOH (8.96 g, 0.224 mol,
1.3 equiv) in THF/MeOH/H.sub.2O (1:1:1 by volume, 734 mL, 10 vol)
for 10 h, and then 2N aqueous HCl was add into the flask until the
pH=7 to quench the reaction. The organic solvent was removed by
vacuum distillation, and the product was collected by filtration.
After trituration in petroleum ether (146 mL, 2 vol),
3-((bis-tert-butoxycarbonyl)amino)-2-(4-chlorophenyl)acrylic acid
(48.0 g, 70% yield) was obtained as white powder. .sup.1H NMR (400
MHz, CD.sub.3CN) .delta.: 7.54 (s, 1H), 7.37 (d, J=8.0 Hz, 2H),
7.17 (d, J=8.0 Hz, 2H), 1.31 (s, 18H); MS-ESI (m/z): [M+Na].sup.+
420.0.
(S)-3-((bis-tert-butoxycarbonyl)amino)-2-(4-chlorophenyl)propanoic
acid
[0109] To the suspension of the LiBF.sub.4 (4.67 g, 0.05 mol, 1.0
equiv) and
3-((bis-tert-butoxycarbonyl)amino)-2-(4-chloro-phenyl)acrylic acid
5 (20 g, 0.05 mol, 1 equiv) in ethanol (400 mL, 20 vol), the
catalyst [(S)-BINAP-RuCl(benzene)]Cl (0.44 g, 0.0005 mol, 0.01
equiv) was added under a nitrogen atmosphere. After vacuum
degassing and hydrogen purging three times, the reaction mixture
was stirred at 55.degree. C. under hydrogen atmosphere (50 psi) for
24 h and filtered through Celite to remove the metal catalyst. The
filtrate was concentrated to dryness under reduced pressure to
afford the pure product
(S)-3-((bis-tert-butoxycarbonyl)amino)-2-(4-chlorophenyl)propanoic
acid (20.1 g, >99% yield and 95.9% ee) as pale solid. .sup.1H
NMR (400 MHz, CDCl.sub.3) .delta.: 7.30 (s, 4H), 3.75.about.3.73
(m, 3H), 1.41 (s, 18H); MS-ESI (m/z): [M+Na].sup.+ 422.0.
* * * * *